The goal of this application is to use a novel rat model to study the compounding effects of cigarette smoke and alcohol abuse on susceptibility to severe pneumococcal pneumonia. Pneumonia is a major cause of morbidity and mortality in alcoholics, and the pneumococcus is the most common bacterial cause. Alcoholics have a higher incidence of pneumococcal pneumonia and they have a greater likelihood of developing bacteremia, which increases their mortality rate. Although scientists have studied the deleterious effects of ethanol ingestion on resistance to infectious diseases for years, the concurrent effects of smoking have been ignored. Because 80-90% of alcoholics smoke and >50% of multi-pack/day smokers are alcohol dependent, it is imperative to consider the additional effects of smoking when studying alcohol-induced defects in host defense against respiratory infections. Our hypothesis is that smoking exacerbates the detrimental effects of ethanol ingestion on host defense mechanisms critical for protection against lethal pneumococcal pneumonia. To test this hypothesis, rats will be exposed twice daily to cigarette smoke or room air in whole body chambers. Half of the rats also will be fed ethanol in a liquid diet. In Specific Aim 1, the rats will be infected intranasally, and the numbers of pneumococci reaching their lungs will be quantified by plate-counts. Movement of the organisms into the lungs will be correlated with alterations in the ciliary beat frequency of the rats' tracheal epithelial cells. In Specific Aim 2, novel in vitro assays will be used to determine the effects of ethanol ingestion, with and without smoke exposure, on the ability of the rats' pulmonary neutrophils to phagocytose and kill pneumococci. In Specific Aim 3, quantitative blood cultures will be used to determine the separate and combined effects of smoke exposure and ethanol ingestion on bacteremia development after establishment of pneumonia. Bacteremia will be correlated with mortality for 10-days post-infection with the use of a hypothermia model to predict death and determine the appropriate time for euthanasia.